Background: Antipsychotic response after the
initiation of neuroleptic treatment shows wide variation in
schizophrenic patient populations. In this overview, the authors
suggest that the variance in antipsychotic drug response within
schizophrenia can be reduced by resolving the schizophrenias into
several discrete "endophenotypes," each with different
etiologic underpinnings.

Method: Studies relating differences in the
relative speed or completeness of antipsychotic response to
differences in distribution of 2 biological markers with possible
etiologic significance are reviewed. Such studies had assessed
recently hospitalized, neuroleptic-free patients undergoing
exacerbation of nonaffective psychotic disorders. Prior to
initiation of neuroleptic, the cohort of patients had been
assessed for the quantity of the dopamine metabolite homovanillic
acid in plasma (pHVA) and had undergone the first of 2 magnetic
resonance imaging (MRI) studies for analyses of ventricle
volumes. A second MRI was subsequently performed during a period
of (partial) remission to determine within-patient stability of
ventricular volumes. These selected studies assessed the
distribution of pHVA and distribution of rates of ventricular
change, with non-normal distributions resolved by K-means
clustering. The speed and completeness of neuroleptic-induced
antipsychotic response were related to 3 clusters of patients
delineated by modal distributions of pHVA and of apparent rates
of ventricular change.

Results: At least 3 unique
"endophenotypes" of the "group of the
schizophrenias" can be defined with respect to speed and
completeness of antipsychotic response. Each endophenotype
appears to show at least one unique biological feature that
differentiates it from a normal comparison group. A rapidly
responsive psychosis was associated with excessive production of
dopamine, as identifiable by elevation of pHVA and a
"good-prognosis" course. A delayed-response psychosis
had low-to-normal pHVA, clinically demonstrated persistent
negative symptoms, and was associated with an excessive rate of
change in ventricle volume between exacerbations of psychosis and
(partial) remissions. Finally, a nonresponsive psychosis could be
characterized as having both low-to-normal pHVA and rate of
change of ventricle volumes similar to that of controls.
Additional studies revealed that each of the endophenotypes had
high rates of the psychoses in family members. The good-prognosis
course of the rapidly responsive group of studied patients was
also found in their family members who had psychotic disorders.
Similarly, the prominent negative symptoms of the
delayed-response probands were reflected as a prominent trait in
their family members also afflicted with psychosis. The
endophenotypes tended to "breed true" in terms of
prognosis and negative symptoms.

Conclusion: Major differences in antipsychotic
response patterns appear to be associated with patient and family
characteristics that may be related to differences in the
etiology and consequent pathophysiology of illness.